Medication-Related Osteonecrosis of the Jaw: New Insights into Molecular Mechanisms and Cellular Therapeutic Approaches

In recent years, medication-related osteonecrosis of the jaw (MRONJ) became an arising disease due to the important antiresorptive drug prescriptions to treat oncologic and osteoporotic patients, as well as the use of new antiangiogenic drugs such as VEGF antagonist. So far, MRONJ physiopathogenesis still remains unclear. Aiming to better understand MRONJ physiopathology, the first objective of this review would be to highlight major molecular mechanisms that are known to be involved in bone formation and remodeling. Recent development in MRONJ pharmacological treatments showed good results; however, those treatments are not curative and could have major side effects. In parallel to pharmacological treatments, MSC grafts appeared to be beneficial in the treatment of MRONJ, in multiple aspects: (1) recruitment and stimulation of local or regional endogenous cells to differentiate into osteoblasts and thus bone formation, (2) beneficial impact on bone remodeling, and (3) immune-modulatory properties that decrease inflammation. In this context, the second objective of this manuscript would be to summarize the molecular regulatory events controlling osteogenic differentiation, bone remodeling, and osteoimmunology and potential beneficial effects of MSC related to those aspects, in order to apprehend MRONJ and to develop new therapeutic approaches.

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Current approaches for early detection and treatment of medication-related osteonecrosis of jaw

Orvosi Hetilap ◽

10.1556/oh.2014.30046 ◽

2014 ◽

Vol 155 (49) ◽

pp. 1960-1966

Author(s):

Ágnes Janovszky ◽

Tamás Vereb ◽

Andrea Szabó ◽

József Piffkó

Keyword(s):

Osteonecrosis Of The Jaw ◽

Interdisciplinary Cooperation ◽

Present Knowledge ◽

Therapeutic Interventions ◽

Detection Methods ◽

Therapeutic Approaches ◽

Incomplete Knowledge ◽

Beneficial Effects ◽

Antiangiogenic Drugs ◽

Osteonecrosis Of Jaw

Owing to the increased life expectancy, the incidence of rheumatoid disorders and oncologic cases with bone metastasis has dramatically increased. Despite the beneficial effects of the applied antiresorptive and antiangiogenic drugs (e.g. bisphosphonates), serious side effects such as jaw osteonecrosis may also develop. The aim of the authors was to summarize present knowledge about the possibilities of prevention and treatment in medication-related osteonecrosis of the jaw. Based on literature data, currently used detection methods for medication-related osteonecrosis of the jaw (including their advantages and limitations) are summarized. In addition, novel trends of surgical and adjuvant therapeutic approaches are also reviewed. The authors conclude that possibilities of prevention and efficacy of therapeutic interventions in this disorder are still limited possibly due to an incomplete knowledge of the underlying pathomechanism. An interdisciplinary cooperation for prevention and attentive monitoring in order to decrease the incidence of iatrogenic oral and maxillofacial complications seems to be particularly important. Orv. Hetil., 2014, 155(49), 1960–1966.

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Mesenchymal Stromal Cell Secretome for the Treatment of Immune-Mediated Inflammatory Diseases: Latest Trends in Isolation, Content Optimization and Delivery Avenues

Pharmaceutics ◽

10.3390/pharmaceutics13111802 ◽

2021 ◽

Vol 13 (11) ◽

pp. 1802

Author(s):

Elena Munoz-Perez ◽

Ainhoa Gonzalez-Pujana ◽

Manoli Igartua ◽

Edorta Santos-Vizcaino ◽

Rosa Maria Hernandez

Keyword(s):

Stromal Cells ◽

State Of The Art ◽

Inflammatory Diseases ◽

Therapeutic Approaches ◽

Pharmacological Management ◽

Beneficial Effects ◽

New Therapeutic Approaches ◽

Immune Mediated ◽

High Prevalence ◽

Inflammatory Processes

Considering the high prevalence and the complex pharmacological management of immune-mediated inflammatory diseases (IMIDs), the search for new therapeutic approaches for their treatment is vital. Although the immunomodulatory and anti-inflammatory effects of mesenchymal stromal cells (MSCs) have been extensively studied as a potential therapy in this field, direct MSC implantation presents some limitations that could slow down the clinical translation. Since the beneficial effects of MSCs have been mainly attributed to their ability to secrete a plethora of bioactive factors, their secretome has been proposed as a new and promising pathway for the treatment of IMIDs. Formed from soluble factors and extracellular vesicles (EVs), the MSC-derived secretome has been proven to elicit immunomodulatory effects that control the inflammatory processes that occur in IMIDs. This article aims to review the available knowledge on the MSC secretome, evaluating the advances in this field in terms of its composition, production and application, as well as analyzing the pending challenges in the field. Moreover, the latest research involving secretome administration in IMIDs is discussed to provide an updated state-of-the-art for this field. Finally, novel secretome delivery alternatives are reviewed, paying special attention to hydrogel encapsulation as one of the most convenient and promising strategies.

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Osteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis

10.21203/rs.3.rs-888146/v1 ◽

2021 ◽

Author(s):

Bingzi Dong ◽

Masahiro Hiasa ◽

Itsuro Endo ◽

Yukiyo Ohnishi ◽

Takeshi Kondo ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Bone Formation ◽

Mechanical Loading ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Mechanical Unloading ◽

Enhanced Expression ◽

Wnt Inhibitors ◽

Interleukin 11

Abstract Exercise offers mechanical loading to the bone, while it stimulates energy expenditure in the adipose tissue. Thus, bone may secrete a factor to communicate with adipose tissue in response to mechanical loading. Interleukin (IL)-11 is expressed in the bone, upregulated by mechanical loading, enhances osteogenesis and suppresses adipogenesis. Systemic IL-11 deletion (IL-11−/−) exhibited reduced bone mass, suppressed bone formation response to mechanical loading, enhanced expression of Wnt inhibitors, and suppressed Wnt signaling. Enhancement of bone resorption under mechanical unloading was unaffected. Unexpectedly, IL-11−/− mice showed increased systemic adiposity and glucose intolerance. Osteoblast/osteocyte-specific IL-11 deletion in osteocalcin-Cre;IL-11fl/fl mice showed reduced serum IL-11, blunted bone formation under mechanical loading, and increased systemic adiposity similar to IL-11−/− mice. Adipocyte-specific IL-11 deletion in adiponectin-Cre; IL-11fl/fl mice exhibited no abnormality. Thus, IL-11 from osteoblast/osteocyte controls both osteogenesis and systemic adiposity in response to mechanical loading. These findings may bring new therapeutic approaches to osteoporosis and metabolic syndrome.

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Astaxanthin and Nrf2 signaling pathway: a novel target for new therapeutic approaches

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210505112834 ◽

2021 ◽

Vol 21 ◽

Author(s):

Milad Ashrafizadeh ◽

Zahra Ahmadi ◽

Habib Yaribeygi ◽

Thozhukat Sathyapalan ◽

Amirhossein Sahebkar

Keyword(s):

Signaling Pathway ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Haematococcus Pluvialis ◽

Primary Source ◽

Redox Balance ◽

Protective Effects ◽

Beneficial Effects ◽

New Therapeutic Approaches ◽

Nrf2 Signaling Pathway

: Astaxanthin (AST) is a naturally occurring compound isolated from various sources such as fungi, plants, salmon, and crab. However, Haematococcus Pluvialis, a green alga, is the primary source of this beta carotenoid compound. AST has several favourable biological and pharmacological activities such as antioxidant, anti-inflammatory, anti-tumor, anti-diabetes, hepatoprotective and neuroprotective. Nevertheless, the exact molecular mechanisms of these protective effects of AST are unclear yet. The Nrf2 signaling pathway is one of the critical candidate signaling pathways that may be involved in these beneficial effects of AST. This signaling pathway is responsible for maintaining the redox balance in the physiologic state. Upon nuclear translocation, Nrf2 signaling activates antioxidant enzymes to reduce oxidative stress and protect cells against damage. In the current study, we have reviewed the effects of AST on the Nrf2 signaling pathway, which could potentially be developed as a novel therapeutic approach for the management of various diseases.

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Dual Role of Metallic Trace Elements in Stress Biology—From Negative to Beneficial Impact on Plants

International Journal of Molecular Sciences ◽

10.3390/ijms20133117 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3117 ◽

Cited By ~ 24

Author(s):

Ewa Muszyńska ◽

Mateusz Labudda

Keyword(s):

Trace Elements ◽

Molecular Mechanisms ◽

Plant Protection ◽

Model Systems ◽

Elevated Concentration ◽

Metallic Ions ◽

Beneficial Effects ◽

Metallic Trace Elements ◽

Beneficial Impact ◽

Evolutionary Consequences

Heavy metals are an interesting group of trace elements (TEs). Some of them are minutely required for normal plant growth and development, while others have unknown biological actions. They may cause injury when they are applied in an elevated concentration, regardless of the importance for the plant functioning. On the other hand, their application may help to alleviate various abiotic stresses. In this review, both the deleterious and beneficial effects of metallic trace elements from their uptake by roots and leaves, through toxicity, up to the regulation of physiological and molecular mechanisms that are associated with plant protection against stress conditions have been briefly discussed. We have highlighted the involvement of metallic ions in mitigating oxidative stress by the activation of various antioxidant enzymes and emphasized the phenomenon of low-dose stimulation that is caused by non-essential, potentially poisonous elements called hormesis, which is recently one of the most studied issues. Finally, we have described the evolutionary consequences of long-term exposure to metallic elements, resulting in the development of unique assemblages of vegetation, classified as metallophytes, which constitute excellent model systems for research on metal accumulation and tolerance. Taken together, the paper can provide a novel insight into the toxicity concept, since both dose- and genotype-dependent response to the presence of metallic trace elements has been comprehensively explained.

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BMP-2/β-TCP Local Delivery for Bone Regeneration in MRONJ-Like Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms21197028 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7028

Author(s):

Akihiro Mikai ◽

Mitsuaki Ono ◽

Ikue Tosa ◽

Ha Thi Thu Nguyen ◽

Emilio Satoshi Hara ◽

...

Keyword(s):

Bone Formation ◽

Bone Remodeling ◽

Tooth Extraction ◽

Pathological Condition ◽

Immunohistochemical Analysis ◽

Osteonecrosis Of The Jaw ◽

Control Group ◽

Extraction Socket ◽

Osteoclast Activity ◽

Prevention Studies

Medication-related osteonecrosis of the jaw (MRONJ) is a severe pathological condition associated mainly with the long-term administration of bone resorption inhibitors, which are known to induce suppression of osteoclast activity and bone remodeling. Bone Morphogenetic Protein (BMP)-2 is known to be a strong inducer of bone remodeling, by directly regulating osteoblast differentiation and osteoclast activity. This study aimed to evaluate the effects of BMP-2 adsorbed onto beta-tricalcium phosphate (β-TCP), which is an osteoinductive bioceramic material and allows space retention, on the prevention and treatment of MRONJ in mice. Tooth extraction was performed after 3 weeks of zoledronate (ZA) and cyclophosphamide (CY) administration. For prevention studies, BMP-2/β-TCP was transplanted immediately after tooth extraction, and the mice were administered ZA and CY for an additional 4 weeks. The results showed that while the tooth extraction socket was mainly filled with a sparse tissue in the control group, bone formation was observed at the apex of the tooth extraction socket and was filled with a dense connective tissue rich in cellular components in the BMP-2/β-TCP transplanted group. For treatment studies, BMP-2/β-TCP was transplanted 2 weeks after tooth extraction, and bone formation was followed up for the subsequent 4 weeks under ZA and CY suspension. The results showed that although the tooth extraction socket was mainly filled with soft tissue in the control group, transplantation of BMP-2/β-TCP could significantly accelerate bone formation, as shown by immunohistochemical analysis for osteopontin, and reduce the bone necrosis in tooth extraction sockets. These data suggest that the combination of BMP-2/β-TCP could become a suitable therapy for the management of MRONJ.

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Neuroinflammatory Nexus of Pediatric Epilepsy

Journal of Pediatric Epilepsy ◽

10.1055/s-0038-1668601 ◽

2018 ◽

Vol 07 (02) ◽

pp. 032-039

Author(s):

Shruti Bagla ◽

Alan Dombkowski

Keyword(s):

Inflammatory Mediators ◽

Molecular Mechanisms ◽

Potential Role ◽

Recent Literature ◽

Refractory Epilepsy ◽

Genetic Mutation ◽

Pediatric Epilepsy ◽

Therapeutic Approaches ◽

New Therapeutic Approaches

AbstractA rapidly growing body of evidence supports the premise that neuroinflammation plays an important role in initiating and sustaining seizures in a range of pediatric epilepsies. Clinical and experimental evidence indicates that neuroinflammation is both an outcome and a contributor to seizures. In this manner, seizures that arise from an initial insult (e.g., infection, trauma, and genetic mutation) contribute to an inflammatory response that subsequently promotes recurrent seizures. This cyclic relationship between seizures and neuroinflammation has been described as a “vicious cycle.” Studies of human tissue resected for surgical treatment of refractory epilepsy have reported activated inflammatory and immune signaling pathways, while animal models have been used to demonstrate that key inflammatory mediators lead to increased seizure susceptibility. Further characterization of the molecular mechanisms involved in this cycle may ultimately enable the development of new therapeutic approaches for the treatment of epilepsy. In this brief review, we focus on key inflammatory mediators that have become prominent in recent literature of epilepsy, including newly characterized microRNAs and their potential role in neuroinflammatory signaling.

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Towards new therapeutic approaches for malignant melanoma

Expert Reviews in Molecular Medicine ◽

10.1017/s146239941100202x ◽

2011 ◽

Vol 13 ◽

Cited By ~ 25

Author(s):

Ivan Pacheco ◽

Cristina Buzea ◽

Victor Tron

Keyword(s):

Molecular Mechanisms ◽

Acquired Resistance ◽

Therapeutic Approaches ◽

Term Survival ◽

Therapeutic Modalities ◽

New Therapeutic Approaches ◽

Mirna Genes ◽

Molecular Therapeutics ◽

Multistep Process

Recent progress in understanding the molecular mechanisms of the initiation and progression of melanoma has created new opportunities for developing novel therapeutic modalities to manage this potentially lethal disease. Although at first glance, melanoma carcinogenesis appears to be a chaotic system, it is indeed, arguably, a deterministic multistep process involving sequential alterations of proto-oncogenes, tumour suppressors and miRNA genes. The scope of this article is to discuss the most recent and significant advances in melanoma molecular therapeutics. It is apparent that using single agents targeting solely individual melanoma pathways might be insufficient for long-term survival. However, the outstanding results on melanoma survival observed with novel selective inhibitors of B-RAF, such as PLX4032 give hope that melanoma can be cured. The fact that melanoma develops acquired resistance to PLX4032 emphasises the importance of simultaneously targeting several pathways. Because the most striking feature of melanoma is its unsurpassed ability to metastasise, it is important to implement newer systems for drug delivery adapted from research on stem cells and nanotechnology.

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An Overview of Long Non-Coding (lnc)RNAs in Neuroblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms22084234 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4234

Author(s):

Francesca Baldini ◽

Matilde Calderoni ◽

Laura Vergani ◽

Paola Modesto ◽

Tullio Florio ◽

...

Keyword(s):

Recent Progress ◽

Molecular Mechanisms ◽

Mechanisms Of Action ◽

Biological Functions ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Definitive Therapy ◽

Sporadic Cases ◽

Non Coding Rnas

Neuroblastoma (NB) is a heterogeneous developmental tumor occurring in childhood, which arises from the embryonic sympathoadrenal cells of the neural crest. Although the recent progress that has been done on this tumor, the mechanisms involved in NB are still partially unknown. Despite some genetic aberrations having been identified, the sporadic cases represent the majority. Due to its wide heterogeneity in clinical behavior and etiology, NB represents a challenge in terms of prevention and treatment. Since a definitive therapy is lacking so far, there is an urgent necessity to unveil the molecular mechanisms behind NB onset and progression to develop new therapeutic approaches. Long non-coding RNAs (lncRNAs) are a group of RNAs longer than 200 nucleotides. Whether lncRNAs are destined to become a protein or not, they exert multiple biological functions such as regulating gene expression and functions. In recent decades, different research has highlighted the possible role of lncRNAs in the pathogenesis of many diseases, including cancer. Moreover, lncRNAs may represent potential markers or targets for diagnosis and treatment of diseases. This mini-review aimed to briefly summarize the most recent findings on the involvement of some lncRNAs in NB disease by focusing on their mechanisms of action and possible role in unveiling NB onset and progression.

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Looking for new anabolic treatment from rare diseases of bone formation

Journal of Endocrinology ◽

10.1530/joe-20-0285 ◽

2020 ◽

Author(s):

Michela Rossi ◽

Giulia Battafarano ◽

Viviana De Martino ◽

Alfredo Scillitani ◽

Salvatore Minisola ◽

...

Keyword(s):

Bone Formation ◽

Bone Erosion ◽

Bone Diseases ◽

Therapeutic Approaches ◽

Rare Disorders ◽

Molecular Defects ◽

New Therapeutic Approaches ◽

Anabolic Treatment ◽

Van Buchem Disease ◽

Engelmann Disease

Bone remodelling is a complex mechanism regulated by osteoclasts and osteoblasts and perturbation of this process leads to the onset of diseases, which may be characterized by altered bone erosion or formation. In this review we will describe some bone formation-related disorders as Sclerosteosis, Van Buchem disease, Hypophosphatasia and Camurati-Engelmann disease. In the past decades the research focused on these rare disorders offered the opportunity to understand important pathways regulating bone formation. Thus, the identification of the molecular defects behind the etiopathology of these diseases will open the way for new therapeutic approaches applicable also to the management of more common bone diseases including osteoporosis.

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